The rise in skin blood flow where humans are exposed to whole body heating is mediated by an active vasodilator reflex that is unique in humans. Although a number of vasoactive substances have been identified that may be involved in active cutaneous vasodilation, the identity of the putative vasodilator is not known. Of these potential vasodilator substances, a role for vasoactive intestinal peptide (VIP) and adenosine in active cutaneous vasodilation appears likely and are specifically targeted in the proposed studies. A portion of the active vasodilator reflex is dependent on NO, but the exact role of NO in this response is unclear. Animal research suggests that NO may act synergistically with the unknown vasodilator to elicit full expression of the active vasodilator response, but that NO is not directly involved. These mechanisms of active cutaneous vasodilation have not been investigated in humans. Thus, the overall goal of this application is to systematically investigate the mechanisms that underlie active cutaneous vasodilation in the skin of humans during whole body heating. This overall goal will be met by addressing the following specific questions: 1) What are the roles of cAMP- and cGMP-dependent pathways in active cutaneous vasodilation? 2) Does cGMP augment cAMP-mediated active vasodilation in the skin of humans during whole body heating? 3) Is the cGMP-mediated portion of active cutaneous vasodilation the same or different as the NO-mediated portion of active cutaneous vasodilation? 4) Does NO act synergistically with the unknown vasodilator substance to allow full expression of active cutaneous vasodilation during whole body heat stress in humans? 5) What is the role of VIP in active cutaneous vasodilation in humans? 6) What is the role of adenosine in active cutaneous vasodilation in humans? These questions will be investigated in humans using state-of-the-art techniques. The findings from these studies will significantly advance our understanding of the control of skin blood flow in humans, and will lead to future studies directed at investigating the diminished thermoregulatory capacity in the elderly and patient populations.